Principal Investigator/Program Director (Last, first, middle): Morrisey, Edward, E. RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A3079-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 4092-Morrisey-_Project_Abstract.pdf Mime Type: application/pdf 7. * Project Narrative 5423-Morrisey_Project_narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 630-Morrisey-LITERATURE_CITED.pdf Mime Type: application/pdf 9. Facilities &Other Resources 3370-Morrisey_Resources.pdf Mime Type: application/pdf 10. Equipment 859-Morrisey_-_Major_Equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Morrisey, Edward, E. The lung airways form through a reiterative process of branching morphogenesis with concomitant cellular differentiation that is regulated, in part, through the activity of multiple signal transduction pathways. Accumulating evidence points to a role for both positive and negative signals from these pathways, which are regulated in a spatial and temporal manner during lung morphogenesis. The action of these pathways results in the distinct proximal-distal patterning observed in the lung airways, which is essential for the proper differentiation of airway epithelia into the active gas exchange interface in mammals. We have recently demonstrated a critical role for the Wnt signaling pathway in lung airway development and differentiation. Our studies show that inactivation of Wnt7b results in severe lung hypoplasia resulting from inhibited airway branching as well as defects in mesenchymal proliferation and type 1 cell differentiation. We have more recently demonstrated that inactivation of the canonical Wnt pathway in lung epithelia either by loss of [unreadable]-catenin expression or expression of the Wnt inhibitor dkk1 leads to a loss of distal airway epithelium by acting upstream of essential transcriptional and signaling factors including N-myc, BMP4 and FGF signaling. Furthermore, we have identified the co- receptor complex in lung epithelium that transmits canonical Wnt signals through Wnt7b. Our hypothesis is that Wnt signaling plays a critical role in embryonic lung airway development, primarily through controlling patterning and differentiation of the airway epithelium. Since much is still not understood about the basic mechanisms underlying Wnt signaling in lung epithelial differentiation and development, we propose to further define the role of Wnt signaling by 1) determining the underlying in vivo mechanism involved in canonical Wnt signalings role in proximal-distal airway petterning, 2) determine the role of non-canonical Wnt signaling in the regulation of lung airway morphogenesis and differentiation, and 3) define the cellular mechanism by which both canonical and non-canonical Wnt signaling regulates lung epithelial cell differentiation, motility, and growth. These aims will address the "where", "why", and "how" Wnt signaling controls lung epithelial development, which is critical to a better understanding of how defective lung epithelial differentiation leads to human disease. Project Description Page 6